EP0816357B1 - Dérivés d'indazole substitués - Google Patents

Dérivés d'indazole substitués Download PDF

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EP0816357B1
EP0816357B1 EP97304083A EP97304083A EP0816357B1 EP 0816357 B1 EP0816357 B1 EP 0816357B1 EP 97304083 A EP97304083 A EP 97304083A EP 97304083 A EP97304083 A EP 97304083A EP 0816357 B1 EP0816357 B1 EP 0816357B1
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ethyl
phenyl
pyridin
compound
indazole
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EP0816357A1 (fr
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Anthony Marfat
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Pfizer Inc
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
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    • A61P37/02—Immunomodulators
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention relates to novel indazole analogs that are selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and other inflammatory diseases, central nervous system disorders such as depression and multi-infarct dementia, AIDS, septic shock and other diseases involving the production of TNF.
  • PDE phosphodiesterase
  • TNF tumor necrosis factor
  • This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus (Kidney Int. 37:362, 1990; Kidney Int. 35:494) and central nervous system disorders such as depression and multi-infarct dementia (PCT international application WO 87/06576 (published November 5, 1987)).
  • TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers, Fed. of Euro. Bio. Soc. (FEBS) Letters, 285, 199, (1991)). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al. , Clinical Immunology and Immunopathology, 62, S11, (1992)).
  • the present invention relates to compounds of the formula I and to pharmaceutically acceptable salts thereof, wherein:
  • Preferred compounds of formula I include those wherein R 1 is ethyl and R is cyclopentyl, cyclohexyl, or C 6 -C 10 aryl.
  • R 3 is -(CH 2 ) n (C 6 -C 10 aryl) or -(CH 2 ) n (5-10 membered heteroaryl), wherein n is 0 to 3, and, more preferably, wherein R 3 is phenyl or pyridin-4-yl.
  • R 7 is -(CH 2 ) n (5-10 membered heteroaryl), wherein n is 0 to 3, and, more preferably, wherein R 7 is pyridin-4-yl.
  • Specific embodiments of the compounds of formula I include those wherein the broken line indicates a single bond, R 2 is H, R 3 is phenyl, 3-methyl-phenyl, 4-pyridyl, 2-furyl, 2-thienyl, or 2-methoxy-phenyl, R 5 is H, R 8 is H, and R 7 is 4-pyridyl, 3-methyl-4-imidazolyl, 3,5-dichloro-4-pyridyl, or 4-pyrimidinyl.
  • R 3 is phenyl, 4-methoxy-phenyl, 2-furyl, 2-thienyl, 4-fluoro-phenyl, 4-trifluoromethyl-phenyl or 2-methoxy-phenyl
  • R 8 is H
  • R 7 is 4-pyridyl
  • the present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) comprising a therapeutically effective amount of a compound according to formula I, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • PDE phosphodiesterase
  • TNF tumor necrosis factor
  • the present invention further relates to the preparation of medicaments for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal, such as a human, comprising a therapeutically effective amount of a compound according to formula I, as defined above, or a pharmaceutically acceptable salt thereof.
  • PDE phosphodiesterase
  • TNF tumor necrosis factor
  • the present invention further relates to a pharmaceutical composition for the prevention or treatment of asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebal malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs.
  • This invention further relates to the preparation of medicaments for treating or preventing the foregoing specific diseases and conditions in a mammal, such as a human, comprising a therapeutically effective amount of a compound according to formula I, as defined above, or a pharmaceutically acceptable salt thereof.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties.
  • alkoxy as used herein, unless otherwise indicated, includes -O-alkyl groups wherein alkyl is as defined above.
  • alkanoyl as used herein, unless otherwise indicated, includes -C(O)-alkyl groups wherein alkyl is as defined above.
  • cycloalkyl as used herein, unless otherwise indicated, includes saturated monovalent cyclo hydrocarbon radicals including cyclobutyl, cyclopentyl and cycloheptyl.
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • heterocyclyl includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N.
  • the heterocyclic groups include benzo-fused ring systems and ring systems substituted with an oxo moiety.
  • An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl.
  • Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl.
  • Heterocyclic groups having a fused benzene ring include benzimidazolyl.
  • heteroaryl as used herein, unless otherwise indicated, includes aromatic heterocyclic groups wherein heterocyclic is as defined above.
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I.
  • Certain compounds of formula I may have asymmetric centers and therefore exist in different enantiomeric forms, and certain compounds of formula I may exist as cis and trans isomers. This invention relates to the use of all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
  • the compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • reaction schemes 1-3 illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R, R 1 , R 3 , R 5 , R 7 and R 8 in the reaction schemes are as defined above.
  • step 1 of Scheme 1 the carboxylic acid of formula II, which is available from known commercial sources or can be prepared according to methods known to those skilled in the art, is nitrated under standard conditions of nitration (HNO 3 /H 2 SO 4 , 0°C) and the resulting nitro derivative of formula III is hydrogenated in step 2 of Scheme 1 using standard hydrogenation methods (H 2 -Pd/C under pressure) at ambient temperature (20-25°C) for several hours (2-10 hours) to provide the compound of formula IV.
  • HNO 3 /H 2 SO 4 0°C
  • step 2 of Scheme 1 using standard hydrogenation methods (H 2 -Pd/C under pressure) at ambient temperature (20-25°C) for several hours (2-10 hours) to provide the compound of formula IV.
  • step 3 of scheme 1 the amino benzoic acid of formula IV is reacted with a base such as sodium carbonate under aqueous conditions and gently heated until mostly dissolved.
  • the reaction mixture is chilled to a lower temperature (about 0°C) and treated with sodium nitrate in water. After about 15 minutes, the reaction mixture is slowly transferred to an appropriate container holding crushed ice and a strong acid such as hydrochloric acid. The reaction mixture is stirred for 10-20 minutes and then added, at ambient temperature, to a solution of excess t-butyl thiol in an aprotic solvent such as ethanol.
  • the reaction mixture is acidified to a pH of 4-5 through addition of an inorganic base, preferably saturated aqueous Na 2 CO 3 , and the reaction mixture is allowed to stir at ambient temperature for 1-3 hours. Addition of brine to the reaction mixture, followed by filtration, provides the sulfide of formula V.
  • an inorganic base preferably saturated aqueous Na 2 CO 3
  • step 4 of Scheme 1 the sulfide of formula V is converted to the corresponding indazole carboxylic acid of formula VI by reacting the sulfide of formula V with a strong base, preferably potassium t-butoxide, in dimethyl sulfoxide (DMSO) at ambient temperature. After stirring for several hours (1-4 hours), the reaction mixture is acidified with a strong acid, such as hydrochloric or sulfuric acid, and then extracted using conventional methods.
  • step 5 of Scheme 1 the indazole carboxylic acid of formula VI is converted to the corresponding ester of formula VII by conventional methods known to those skilled in the art.
  • step 6 of Scheme 1 the compound of formula VIII is provided through alkylation of the ester of formula VII by subjecting the ester to conventional alkylation conditions (strong base/various alkylating agents and, optionally, a copper catalyst such as CuBr 2 ) in a polar aprotic solvent, such as tetrahydrofuran (THF), N-methylpyrrolidinone or dimethylformamide (DMF), at ambient or higher temperature (25-200°C) for about 6-24 hrs, preferably about 12 hours.
  • step 7 of Scheme 1 the compound of formula VIII is converted to the corresponding alcohol of formula IX by following conventional methods known to those skilled in the art for reducing esters to alcohols.
  • the reduction is effected through use of a metal hydride reducing agent, such as lithium aluminum hydride, in a polar aproptic solvent at a low temperature (about 0°C).
  • a metal hydride reducing agent such as lithium aluminum hydride
  • the alcohol of formula IX is oxidized to the corresponding aldehyde of formula X according to conventional methods known to those skilled in the art.
  • the oxidation can be effected through use of a catalytic amount of tetrapropylammonium perrutenate and excess N-methylmorpholine-N-oxide, as described in J. Chem. Soc., Chem. Commun., 1625 (1987), in an anhydrous solvent, preferably methylene chloride.
  • Scheme 2 provides an alternative method of preparing the aldehyde of formula X.
  • the compound of formula XI is nitrated using conventional nitration conditions (nitric and sulfuric acid) to provide the compound of formula XII.
  • the nitro derivative of formula XII is reduced to the corresponding amine of formula XIII according to conventional methods known to those skilled in the art.
  • the compound of formula XII is reduced to the amine of formula XIII using anhydrous stannous chloride in an anhydrous aprotic solvent such as ethanol.
  • step 3 of Scheme 2 the amine of formula XIII is converted to the corresponding indazole of formula XIV by preparing the corresponding diazonium tetrafluoroborates as described in A. Roe, Organic Reactions, Vol. 5, Wiley, New York, 1949, pp. 198-206, followed by phase transfer catalyzed cyclization as described in R. A. Bartsch and I. W. Yang, J. Het. Chem. 21, 1063 (1984).
  • step 4 of Scheme 2 alkylation of the compound of formula XIV is performed using standard methods known to those skilled in the art (i.e. strong base, polar aprotic solvent and an alkyl halide) to provide the N-alkylated compound of formula XV.
  • step 5 of Scheme 2 the compound of formula XV is subjected to metal halogen exchange employing an alkyl lithium, such as n-butyl lithium, in a polar aprotic solvent, such as THF, at low temperature (-50°C to 100°C (-78°C preferred)) followed by quenching with DMF at low temperature and warming to ambient temperature to provide the aldehyde intermediate of formula X.
  • metal halogen exchange employing an alkyl lithium, such as n-butyl lithium, in a polar aprotic solvent, such as THF, at low temperature (-50°C to 100°C (-78°C preferred)) followed by quenching with DMF at low temperature and warming to ambient temperature to provide the aldehyde intermediate of formula X.
  • Scheme 3 illustrates the preparation of the compounds of formula I.
  • step 1 of Scheme 3 the intermediate aldehyde of formula X is reacted with a compound of formula R 3 -Li, wherein R 3 is as defined above, in THF at a temperature within the range of about -78°C to ambient temperature (20-25°C) for a period of about 30 minutes to 3 hours to provide the alcohol intermediate of formula XVI.
  • step 2 of Scheme 3 the intermediate of formula XVI is reacted in the presence of tetrapropylammonium perruthenate (VII) and 4A molecular sieves in N-methylmorpholine N-oxide and methylene chloride at ambient temperature for about 1 hour to provide the ketone intermediate of formula XVII.
  • VII tetrapropylammonium perruthenate
  • 4A molecular sieves in N-methylmorpholine N-oxide and methylene chloride at ambient temperature for about 1 hour to provide the ketone intermediate of formula X
  • the ketone intermediate of formula XVII can be synthesized by reacting the intermediate of formula XV with a compound of formula R 3 -CN, wherein R 3 is as defined above, in the presence of n-butyllithium in THF at a temperature of about -78°C for about 45 minutes and then warming the mixture to -10°C for about 30 minutes to provide the intermediate of formula XVII.
  • step 3 of Scheme 3 the intermediate of formula XVII is reacted with a compound of formula CHR 5 R 7 R 8 , wherein R 5 , R 7 , and R 8 are as defined above, in the presence of n-butyllithium in THF at a temperature of about -78°C for about 1 hour and then warming the mixture to ambient temperature for about 30 minutes to provide the intermediate of formula XVIII.
  • step 4 of Scheme 3 the intermediate of formula XVIII is reacted in the presence of p-toluenesulfonic acid and toluene and heated to reflux for about 7 hours to provide the compound of formula XIX which corresponds to the compound of formula I wherein the dashed line indicates a double bond.
  • step 5 of Scheme 3 the compound of formula XIX is hydrogenated in the presence of palladium on carbon in ethanol and triethylamine under 25 psi H 2 at ambient temperature for about 3.5 hours followed by separation of the reaction product and dissolution of the reaction product in ether and 1 N hydrochloric acid to provide the compound of formula XX.
  • the compound of formula XX corresponds to the compound of formula I wherein the dashed line indicates a single bond.
  • the compounds of formula I can also be prepared following one or more synthetic methods that are disclosed in published patent applications.
  • those skilled in the art can prepare the compounds of formula I using analogous synthetic methods that have been described for compounds in which a phenyl ring is substituted for the indazole ring in the compounds of formula I.
  • the compounds of formula I wherein R 3 and R 7 are independently -(CH 2 ) n (C 6 -C 10 aryl) or -(CH 2 ) n (5-10 membered heteroaryl) and R 8 is H or C 1 -C 6 alkyl can be prepared by following analogous synthetic methods disclosed in WO 94/14742 and WO 94/14800, both of which are referred to above.
  • R 3 and R 7 are independently H, C 1 -C 6 alkyl, cyano, cyanomethyl, -CO 2 (CH 2 ) n (C 6 -C 10 aryl), -C(Y)NR 5 R 6 or -C(Y)NR 5 (CH 2 ) n (C 6 -C 10 aryl) and R 8 is -(CH 2 ) p (C 6 -C 10 aryl) or -(CH 2 ) p (C 6 -C 10 heteroaryl)
  • R 8 is -(CH 2 ) p (C 6 -C 10 aryl) or -(CH 2 ) p (C 6 -C 10 heteroaryl)
  • R 3 is -(CH 2 ) n (C 6 -C 10 aryl) or -(CH 2 ) n (5-10 membered heteroaryl)
  • R 7 is 2-oxo-pyridyl, 3-oxo-pyridyl, 4-oxo-pyridyl, 2-oxo-pyrrolyl,4-oxo-thiazolyl,4-oxo-piperidyl,2-oxp-quinolyl,4-oxo-quinolyl,1-oxo-isoquinolyl, 4-oxo-oxazolyl, 5-oxo-pyrazolyl, 5-oxo-isoxazolyl, or 4-oxo-isoxazolyl, can be prepared by following analogous methods disclosed in WO 95/17392, which is referred to above.
  • the compounds of formula I wherein R 3 is -(CH 2 ) n (C 6 -C 10 aryl) or -(CH 2 ) n (5-10 membered heteroaryl) optionally substituted by an R 10 substituent, and R 7 is -(CH 2 ) n (C 6 -C 10 aryl) or -(CH 2 ) n (5-10 membered heteroaryl), can be prepared by following analogous methods disclosed in WO 95/17399, which is referred to above.
  • the compounds of formula I wherein R 3 is benzyloxy and R 7 is -(CH 2 ) n (5-10 membered heteroaryl) can be prepared by following analogous methods disclosed in WO 95/35284, which is referred to above.
  • the compounds of formula I can be resolved into separate enantiomers by using a chiral LC technique according to the following conditions: column: Chiralcel® OD (250 x 4.6 mm); Mobile phase: 50:50:0.1 (Hexane:2-propanol:diethylamine); Flow rate: 1 mL/minute; detection: UV (230 nm); temperature: ambient (20-25°C); injection volume: 20 ⁇ L.
  • the compounds of formula I can also be resolved into separate enantiomers according to other techniques familiar to those skilled in the art, including those described in J. March, Advanced Organic Chemistry, (4th Edition, J. Wiley & Sons), 1992, pages 118-125.
  • the compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to humans or animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Pharmaceutically acceptable salts of amino groups include hydrochloride (preferred), hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
  • Cationic salts of the compounds of formula I are similarly prepared except through reaction of a carboxy group, such as where R 6 is carboxy, with an appropriate cationic salt reagent such as sodium, potassium, calcium, magnesium, ammonium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
  • an appropriate cationic salt reagent such as sodium, potassium, calcium, magnesium, ammonium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
  • oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof are generally in the range of 0.1 to 1000 mg daily, in single or divided doses, for an average adult patient (70 kg).
  • the active compounds can be administered in single or divided doses.
  • Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
  • Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required.
  • the dosage is generally formulated as a 0.1 to 1% (w/v) solution.
  • the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg in single or divided doses.
  • dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg in single or divided doses.
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated.
  • the person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic.
  • the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
  • the therapeutic compounds may also be administered to a mammal other than a human.
  • the dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated.
  • the therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench.
  • the therapeutic compounds may also be administered to animals by injection or as an implant.
  • Such formulations are prepared in a conventional manner in accordance with standard veterinary practice.
  • the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
  • the ability of the compounds of formula I or the pharmaceutically acceptable salts thereof to inhibit PDE IV may be determined by the following assay.
  • a flow rate of 1 ml/minute is used to apply the sample to the column, followed by a 2 ml/minute flow rate for subsequent washing and elution.
  • Sample is eluted using an increasing, step-wise NaCI gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are collected. Fractions are assayed for specific PDE IV activity determined by [ 3 H]cAMP hydrolysis and the ability of a known PDE IV inhibitor (e.g. rolipram) to inhibit that hydrolysis. Appropriate fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at -20°C until use.
  • PDE IV inhibitor e.g. rolipram
  • DMSO dimethylsulfoxide
  • the reaction tubes are shaken and placed in a water bath (37°C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water bath for 4 minutes.
  • Washing buffer 0.5 ml, 0.1M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1M naci, pH 8.5
  • HEPES 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid
  • naci pH 8.5
  • [ 3 H]cAMP is washed with 2 x 6 ml washing buffer, and [ 3 H]5'AMP is then eluted with 4 ml of 0.25M acetic acid. After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, vortexed and counted for [ 3 H].
  • % inhibition 1 - average cpm (test compound - average cmp (blank) average cpm (control) - average cpm (blank) IC 50 is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [ 3 H]cAMP to [ 3 H]5'AMP.
  • Peripheral blood (100 mls) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA).
  • Mononuclear cells are isolated by FICOLL/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1 x 10 6 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 10 6 cells in 1.0 ml in 24-well plates. The cells are incubated at 37°C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing.
  • EDTA ethylenediaminetetraacetic acid
  • Test compounds (10 ⁇ l) are then added to the cells at 3-4 concentrations each and incubated for 1 hour.
  • LPS (10 ⁇ l) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37°C.
  • TNF was analyzed by a sandwich EUSA (R&D Quantikine Kit). IC 50 determinations are made for each compound based on linear regression analysis.
  • reaction mixture was cooled to room temperature, diluted with 50 mL ethyl acetate, washed 2 x 15 mL 1N NaOH, 1 x 15 mL H 2 O, 1 x 15 mL brine, and dried over Na 2 SO 4 .
  • the reaction mixture was diluted with 200 mL H 2 O and 100 mL 1N NaOH, and extracted 2 x 100 mL ethyl acetate.
  • the organic extracts were combined, washed 1 x 50 mL each H 2 O, brine, and dried over Na 2 SO 4 . Filtration, concentration of filtrate and drying gave a yellow oil, which was purified on a silica gel column (2.5% CH 3 OH/CH 2 Cl 2 ) to give 0.92 g (95%) of a white amorphous solid.
  • a small sample was crystallized from ethyl acetate/hexanes to give 27 mg white needles: mp 134-136°C; Anal. calcd for C 27 H 27 N 3 : C, 82.41; H, 6.92; N, 10.68; Found: C, 82.31; H, 7.17; N, 10.80.

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Claims (14)

  1. Composé répondant à la formule
    Figure 00390001
    ou un de ses sels pharmaceutiquement acceptable, dans lequel :
    la ligne en traits interrompus indique une liaison simple ou double ;
    X1 est un radical -CR2R3 lorsque cette ligne en traits interrompus indique une liaison simple ou un radical -CR3 lorsque cette ligne en traits interrompus indique une liaison double ;
    X2 est un radical -CR5R7R8 lorsque cette ligne en traits interrompus indique une liaison simple ou un radical -CR7R8 lorsque cette ligne en traits interrompus indique une liaison double ;
    R est un radical-(CH2)m(cycloalkyle en C8 à C7), dans lequel m est un nombre de 0 à 2, ou un groupe aryle en C6 à C10 ;
    R1 est un groupe alkyle en C1 à C7 ;.
    R2 est H, un groupe hydroxy, un groupe halogéno ou un groupe -OR9 ;
    R3 est un groupe-(CH2)n(aryle en C6 à C10) ou un groupe -(CH2)n(hétéroaryle à 5 à 10 maillons), dans lequel n est un nombre de 0 à 3, et R3 est substitué si on le désire par 1 à 3 groupes R4 ;
    chacun des radicaux R4 est choisi indépendamment parmi un groupe halogéno, cyano, nitro, alkyle en C1 à C6, alcényle en C2 à C6 ou -OR5 ;
    chacun des radicaux R5 est indépendamment H ou un groupe alkyle en C1 à C6 ;
    R7 est R3 ;
    R8 est R5 ; et
    R9 est un groupe formyle, carbamoyle, thiocarbamyle ; alkyle en C1 à C6, alcényle en C2 à C6, (alkoxy en C1 à C4) alkyle en C1 à C4, ou alcanoyle en C1 à C6, dans lequel les parties alkyle de ces groupes R9 sont substituées si on le désire par 1 à 3 substituants choisis indépendamment parmi les groupes halogéno, hydroxy et alkoxy en C1 à C4.
  2. Composé selon la revendication 1, dans lequel R1 est un groupe éthyle et R est un groupe cyclopentyle, cyclohexyle ou aryle en C6 à C10.
  3. Composé selon la revendication 2, dans lequel R3 est un groupe -(CH2)n(aryle en C6 à C10) ou un groupe -(CH2)n(hétéroaryle à 5 à 10 maillons), dans lequel n est un nombre de 0 à 3.
  4. Composé selon la revendication 3, dans lequel R3 est un groupe phényle ou pyridin-4-yle.
  5. Composé selon la revendication 2, dans lequel R7 est un groupe -(CH2)n(hétéroaryle à 5 à 10 maillons), dans lequel n est un nombre de 0 à 3.
  6. Composé selon la revendication 5, dans lequel R7 est un groupe pyridin-4-yle.
  7. Composé selon la revendication 1, dans lequel la ligne en traits interrompus indique une liaison simple, R2 est H, R3 est un groupe phényle, 3-méthyl-phényle, 4-pyridyle, 2-furyle, 2-thiényle ou 2-méthoxy-phényle, R5 est H, R8 est H, et R7 est un groupe 4-pyridyle, 3-méthyl-4-imidazolyle, 3,5-dichloro-4-pyridyle ou 4-pyrimidinyle.
  8. Composé selon la revendication 1, dans lequel la ligne en traits interrompus indique une liaison double, R3 est un groupe phényle, 4-méthoxy-phényle, 2-furyle, 2-thiényle, 4-fluoro-phényle, 4-trifluorométhyl-phényle ou 2-méthoxy-phényle, R8 est H, et R7 est un groupe 4-pyridyle.
  9. Composé selon la revendication 1, dans lequel ce composé est choisi dans le groupe constitué :
    du 1-(-cyclopentyl-3-éthyl-1H-indazol-6-yl)-1,2-di-pyridin-4-yl-éthanol ;
    du 1-cyclopentyl-6-(1,2-di-pyridin-4-yl-vinyl)-3-éthyl-1H-indazole ;
    du 1-cyclopentyl-6-(1,2-di-pyridin-4-yl-éthyl)-3-éthyl-1H-indazole;
    du 1-(-cyclopentyl-3-éthyl-1H-indazol-6-yl)-1-phényl-2-pyridin-4-yl-éthanol;
    du 1-(-cyclopentyl-3-éthyl-6-(1-phényl-2-pyridin-4-yl-vinyl)-1H-indazole ;
    du 1-(-cyclopentyl-3-éthyl-6-(1-phényl-2-pyridin-4-yl-éthyl)-1H-indazole ;
       et des sels pharmaceutiquement acceptables des composés qui précèdent.
  10. Composé selon la revendication 1, dans lequel ce composé est choisi dans le groupe constitué :
    du 1-(1-cyclohexyl-3-éthyl-1H-indazol-6-yl)-1,2-di-pyridin-4-yl-éthanol ;
    du 1-cyclohexyl-6-(1,2-di-pyridin-4-yl-vinyl)-3-éthyl-1H-indazole ;
    du 1-1-cyclohexyl-6-(1,2-di-pyridin-4-yl-éthyl) -3-éthyl-1H-indazole ;
    du 1-(1-cyclohexyl-3-éthyl-1H-indazol-6-yl)-1-phényl-2-pyridin-4-yl-éthanol ;
    du 1-cyclohexyl-3-éthyl-6-(1-phényl-2-pyridin-4-yl-vinyl)-1H-indazole ;
    du 1-cyclohexyl-3-éthyl-6-(1-phényl-2-pyridin-4-yl-éthyl)-1H-indazole ;
       et des sels pharmaceutiquement acceptables des composés qui précèdent.
  11. Composition pharmaceutique pour l'inhibition de la phosphodiestérase (PDE) type IV ou la production du facteur de nécrose des tumeurs (TNF) comprenant une quantité thérapeutiquement efficace d'un composé selon la revendication 1 et d'un support pharmaceutiquement acceptable.
  12. Utilisation d'une quantité thérapeutiquement efficace d'un composé selon la revendication 1 pour la préparation d'un médicament pour l'inhibition de la phosphodiestérase (PDE) type IV ou la production du facteur de nécrose des tumeurs (TNF) chez un mammifère.
  13. Composition pharmaceutique pour la prévention ou le traitement de l'asthme, de l'inflammation articulaire, de l'arthrite rhumatoïde, de l'arthrite goutteuse, de la spondylite rhumatoïde, de l'ostéoporose et d'autres états arthritiques, de la septicémie, du choc septique, du choc endotoxique, de la septicémie Gram négative, du syndrome de choc toxique, du syndrome de détresse respiratoire aiguë, de l'accès cérébral, de l'inflammation pulmonaire chronique, de la silicose, de la sarcoïdase pulmonaire, des maladies de la résorption osseuse, des plaies de reperfusion, de la réaction de la greffe sur l'hôte, des rejets d'allogreffes, de la fièvre et des myalgies dues à une infection, telles que l'influenza, la cachexie secondaire à l'infection ou à une affection maligne, la cachexie secondaire due au syndrome d'immunodéficience acquise humaine (SIDA), SIDA, HIV, ARC (complexe lié au SIDA), formation chéloïdienne, formation de tissu cicatriciel, maladie de Crohn, colite ulcéreuse, pyrèse, sclérose multiple, diabète sucré du type 1, diabète insipide, diabète auto-immun, lupus érythémateux systémique, bronchite, maladie obstructive chronique des voies respiratoires, psoriasis, maladie de Bechet, purpura anaphylactoïde, glomérulonéphrite chronique, inflammation des intestins, leucémie, rhinite allergique, dermatite, dépression ou démence à accès multiples, comprenant une quantité thérapeutiquement efficace d'un composé selon la revendication 1 avec un support pharmaceutiquement acceptable.
  14. Utilisation d'une quantité thérapeutiquement efficace d'un composé selon la revendication 1 pour la préparation d'un médicament pour le traitement ou la prévention de l'asthme, de l'inflammation articulaire, de l'arthrite rhumatoïde, de l'arthrite goutteuse, de la spondylite rhumatoïde, de l'ostéoporose et d'autres états arthritiques, de la septicémie, du choc septique, du choc endotoxique, de la septicémie Gram négative, du syndrome de choc toxique, du syndrome de détresse respiratoire aiguë, de l'accès cérébral, de l'inflammation pulmonaire chronique, de la silicose, de la sarcoïdase pulmonaire, des maladies de la résorption osseuse, des plaies de reperfusion, de la réaction de la greffe sur l'hôte, des rejets d'allogreffes, de la fièvre et des myalgies dues à une infection, telles que l'influenza, la cachexie secondaire à l'infection ou à une affection maligne, la cachexie secondaire due au syndrome d'immunodéficience acquise humaine (SIDA), SIDA, HIV, ARC (complexe lié au SIDA), formation chéloïdienne, formation de tissu cicatriciel, maladie de Crohn, colite ulcéreuse, pyrèse, sclérose multiple, diabète sucré du type 1, diabète insipide, diabète auto-immun, lupus érythémateux systémique, bronchite, maladie obstructive chronique des voies respiratoires, psoriasis, maladie de Bechet, purpura anaphylactoïde, glomérulonéphrite chronique, inflammation des intestins, leucémie, rhinite allergique, dermatite, dépression ou démence à accès multiples chez un mammifère.
EP97304083A 1996-06-27 1997-06-11 Dérivés d'indazole substitués Expired - Lifetime EP0816357B1 (fr)

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BR0110302A (pt) 2000-04-18 2003-01-14 Agouron Pharma Compostos de pirazol para inibição de proteìnas cinase, sal e pró-droga farmaceuticamente aceitável, metabólito farmaceuticamente ativo ou sal farmaceuticamente aceitável de metabólito, composição farmacêutica, método de tratamento de condição doentia em mamìferos mediada pela atividade de proteìna cinase, método de modulação ou inibição da atividade de um receptor de proteìna cinase
JP4216720B2 (ja) * 2001-10-19 2009-01-28 サントル・オスピタリエ・レジオナル・エ・ユニヴェルシタイル・ドゥ・トゥール 抗体処置応答を評価するための方法および組成物
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US8715664B2 (en) 2005-05-16 2014-05-06 Abbvie Biotechnology Ltd. Use of human TNFα antibodies for treatment of erosive polyarthritis
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EP1807082A4 (fr) * 2004-10-26 2010-12-01 Janssen Pharmaceutica Nv Composes inhibiteurs du facteurs xa
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EP1928928B1 (fr) * 2005-09-22 2018-02-21 Huntsman International Llc Procédé de préparation de polyisocyanate
US9605064B2 (en) 2006-04-10 2017-03-28 Abbvie Biotechnology Ltd Methods and compositions for treatment of skin disorders
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EP2171451A4 (fr) 2007-06-11 2011-12-07 Abbott Biotech Ltd Procédés de traitement de l'arthrite idiopathique juvénile
WO2010120854A1 (fr) * 2009-04-15 2010-10-21 Glaxosmithkline Llc Composés chimiques
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